This invention relates to benzylketones and processes for their preparation, pharmaceutical compositions containing them and pharmaceutical methods using them. These compounds have shown activity as inhibitors of the enzyme phospholipase A.sub.2. They are also intermediates in the synthesis of other PLA.sub.2 inhibitors.
The important role of phospholipase A.sub.2 in the biosynthesis of prostaglandins and leukotrienes indicates that inhibitors of phospholipase A.sub.2 may be valuable therapeutic agents having wide applicability in inflammatory, allergic, and other phospholipase A.sub.2 mediated conditions in mammals. Although some currently available anti-inflammatory agents show activity against phospholipase A.sub.2 or other enzymes of the "arachidonic acid cascade", there is a continuing need for safer and more effective drugs capable of treating inflammatory and/or allergic diseases.
U.S. Pat. No. 4,239,780 (issued to D. P. Wallach on Dec. 16, 1980) discloses the use for treating phospholipase A.sub.2 mediated conditions of compounds of the formula: ##STR1## whereinR.sub.1 is 4--Cl, 4--CF.sub.3, H, or 2-- or 4--CH.sub.3 ;
R.sub.2 is CH.sub.3 --O--, --CH.sub.2 --OH, or H; PA1 R.sub.3 is H or CH.sub.3 ; and PA1 R.sub.4 is F or Cl. PA1 n is 2 to 5; PA1 X is NH, NR.sup.2, O, S(O).sub.p, and R.sup.2 is methyl or ethyl, and p is 0, 1, or 2; PA1 R is C.sub.6 -C.sub.25 alkyl, pyridyl, aryl or substituted aryl of the formula: ##STR4## where W is H, F, Cl, Br, hexafluoroisopropanol, phenyl, C.sub.1 -C.sub.18 alkyl, OR.sup.3, SR.sup.3, and R.sup.3 is methyl or ethyl; or PA1 R is benzhydryl, phenyl-(4-pyridyl)methyl, or C.sub.7 -C.sub.25 alkaryl or substituted alkaryl where the substitution is on the aromatic moiety and is F, Cl, Br, OR.sup.3, S(O).sub.r R.sup.3, or C.sub.1 -C.sub.10 alkyl, where R.sup.3 is methyl or ethyl, and r is 0, 1, or 2; PA1 a. when X is N--CH.sub.3 or N--C.sub.2 H.sub.5, R must be hydroxyhexafluoroisopropylphenyl; PA1 b. when X is O, n can not be 2; PA1 c. when X is S(O).sub.p, W cannot be methyl or ethyl; PA1 d. when X is NH, R cannot be phenyl, benzyl, 1-methylbenzyl, phenethyl, substituted phenylethyl, or pyridyl; and PA1 e. when r is benzhydryl, Z must be F. PA1 n is 2 to 5; PA1 X is NH or S(O).sub.p, and p is 0 or 2; PA1 R is C.sub.6 -C.sub.25 alkyl, pyridyl, aryl, or substituted aryl of the formula: ##STR6## where W is H, hexafluoroisopropanol, phenyl, C.sub.1 -C.sub.14 alkyl, OR.sup.3, or SR.sup.3 ; where R.sup.3 is methyl or ethyl; or PA1 R is 2-naphthalenylethyl, dehydroabietyl, phenyl-(4-pyridyl)methyl, 4-methoxyl-naphthalenylmethyl, benzyl, 6-methoxy-2-naphthalenylethyl, 1-naphthalenylethyl, 1-naphthalenylmethyl, benzhydryl, or 1-benzyl-4-pyridinyl-ethyl. PA1 Ar is phenyl, 4-fluorophenyl, 4-methoxyphenyl, or 4-methylthiophenyl; PA1 n is 2 or 3; PA1 X is NH or S; PA1 R is 4-(hexafluoroisopropyl)phenyl, cyclohexane methyl, myrtanyl, 2-naphthalenylethyl, 1-naphthalenylethyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, hexyl, heptyl, octyl, decyl, undecyl, dodecylphenyl, tetradecyl, hexyldecyl, octadecyl, phenyl-(4-pyridyl)methyl, 4-tert-butylphenyl, 4-n-butylphenyl, 4-n-hexylphenyl, 4-decylphenyl, 4dodecylphenyl, 6-methoxy-2-naphthalenylethyl, 4-methoxy-1-naphthalenylmethyl, 4-biphenylmethyl, dehydroabietyl, or 4-pyridyl; 2-(1-adamantyl)ethyl, 1-methyl-1-(1-adamantyl)-methyl, PA1 X is NH, R cannot be 2-, 3-, or 4-methylphenyl, or 4-pyridyl. PA1 a. 1-(4-Fluorophenyl)-3-[(phenyl)(4-pyridyl)methylamino]-1-propanone Dihydrochloride. PA1 b. 1-(4-Fluorophenyl)-3-(undecylamino)-1-propanone Hydrochloride. PA1 c. 1-(4-Fluorophenyl)-3-(decylamino)-1-propanone Hydrochloride. PA1 d. 4-([1,4a-Dimethyl-1,2,3,4,4a,9,10,10a-octahydro-7-(1-methylethyl)-1-phenan threnyl]-methylamino]-1-(4-fluorophenyl)-1-butanone 4-Methylbenzene sulfonate. PA1 e. 1-(4-Fluorophenyl)-3-([1,4a-dimethyl-7-(1-methylethyl)-1,2,3,4,4a,9,10,10a -octahydro-1-phenanthrenyl-1-yl]methylamino]-1-propanone 4-Methylbenzene sulfonate. PA1 f. 1-(Fluorophenyl)-4-(3-methylphenylthio)-1-butanone. PA1 g. 1-(Fluorophenyl)-4-(4-methylphenylthio)-1-butanone.
These compounds and their activities as inhibitors of phospholipase A.sub.2 are also described in D. P. Wallach and V. J. R. Brown, Biochemical Pharmacology, 30, 1315 (1981).